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Salt and fluid absorption and secretion are two processes that are fundamental to epithelial function and whole body fluid homeostasis, and as such are tightly regulated in epithelial tissues. The CFTR anion channel plays a major role in regulating both secretion and absorption in a diverse range of epithelial tissues, including the airways, the GI and reproductive tracts, sweat and salivary glands. It is not surprising then that defects in CFTR function are linked to disease, including life-threatening secretory diarrhoeas, such as cholera, as well as the inherited disease, cystic fibrosis (CF), one of the most common life-limiting genetic diseases in Caucasian populations. More recently, CFTR dysfunction has also been implicated in the pathogenesis of acute pancreatitis, chronic obstructive pulmonary disease (COPD), and the hyper-responsiveness in asthma, underscoring its fundamental role in whole body health and disease. CFTR regulates many mechanisms in epithelial physiology, such as maintaining epithelial surface hydration and regulating luminal pH. Indeed, recent studies have identified luminal pH as an important arbiter of epithelial barrier function and innate defence, particularly in the airways and GI tract. In this chapter, we will illustrate the different operational roles of CFTR in epithelial function by describing its characteristics in three different tissues: the airways, the pancreas, and the sweat gland.

The pancreas is made from two distinct components: the exocrine pancreas, a reservoir of digestive enzymes, and the endocrine islets, the source of the vital metabolic hormone insulin. Human islets possess limited regenerative ability; loss of islet β-cells in diseases such as type 1 diabetes requires therapeutic intervention. The leading strategy for restoration of β-cell mass is through the generation and transplantation of new β-cells derived from human pluripotent stem cells. Other approaches include stimulating endogenous β-cell proliferation, reprogramming non-β-cells to β-like cells, and harvesting islets from genetically engineered animals. Together these approaches form a rich pipeline of therapeutic development for pancreatic regeneration.

This brand new updated edition of the most comprehensive reference book on pancreatic disease details the very latest knowledge on genetics and molecular biological background in terms of anatomy, physiology, pathology, and pathophysiology for all known disorders. Included for the first time, are two brand new sections on the key areas of Autoimmune Pancreatitis and Benign Cystic Neoplasms. In addition, this edition is filled with over 500 high-quality illustrations, line drawings, and radiographs that provide a step-by-step approach to all endoscopic techniques and surgical procedures. Each of these images can be downloaded via an online image bank for use in scientific presentations. Every existing chapter in The Pancreas: An Integrated Textbook of Basic Science, Medicine and Surgery, 3rd Edition has been thoroughly revised and updated to include the many changes in clinical practice since publication of the current edition. The book includes new guidelines for non-surgical and surgical treatment; new molecular biologic pathways to support clinical decision making in targeted treatment of pancreatic cancer; new minimally invasive surgical approaches for pancreatic diseases; and the latest knowledge of neuroendocrine tumors and periampullary tumors. * The most encyclopedic book on the pancreas—providing outstanding and clear guidance for the practicing clinician * Covers every known pancreatic disorder in detail including its anatomy, physiology, pathology, pathophysiology, diagnosis, and management * Completely updated with brand new chapters * Over 500 downloadable illustrations * An editor and author team of high international repute who present global best-practice The Pancreas: An Integrated Textbook of Basic Science, Medicine and Surgery, 3rd Edition is an important book for gastroenterologists and gastrointestinal surgeons worldwide.

In 2006, it was reported that BM is a source of myofibroblast-like cells in fibrotic liver tissue, but the involvement of these cells in the progression of liver fibrosis remains questionable as their contribution to collagen synthesis appears to be limited. 19 20 Recent studies have now also addressed the role of BM-derived cells in pancreatic regeneration and fibrosis. 21 22 Using a similar experimental approach, namely the transfer of green fluorescent protein (GFP)-expressing BM cells to lethally irradiated small rodents followed by the induction of chronic pancreatitis with cerulein or dibutyltin dichloride, it was consistently shown that BM-derived cells did home to the pancreas. 21 22 In both studies, the induction of chronic pancreatitis was found to be associated with an increase in the number of GFP-expressing PSC. [...]therapeutic strategies would be expected to reduce the fibrosis of chronic pancreatitis, thereby retarding the development of exocrine and endocrine insufficiency, and interrupt the interaction of PSC in the stromal reaction with pancreatic cancer cells, thereby inhibiting tumour progression and improving the otherwise dismal prognosis of this disease. [...]at present, the field of PSC research is dynamic and wide open, with significant potential for novel discoveries and major breakthroughs that could have a lasting impact on the treatment of patients with pancreatic diseases.

Diseases intrinsic to the pancreas such as pancreatitis, pancreatic cancer and type 1 diabetes mellitus impart substantial health and financial burdens on society but identification of novel mechanisms contributing to these pathologies are slow to emerge. A novel area of research suggests that pancreatic-specific disorders might be modulated by the gut microbiota, either through a local (direct pancreatic influence) or in a remote (nonpancreatic) fashion. In this Perspectives, we examine literature implicating microorganisms in diseases of the pancreas, specifically pancreatitis, type 1 diabetes mellitus and pancreatic ductal adenocarcinoma. We also discuss evidence of an inherent pancreatic microbiota and the influence of the intestinal microbiota as it relates to disease association and development. In doing so, we address pitfalls in the current literature and areas of investigation that are needed to advance a developing field of research that has clinical potential to reduce the societal burden of pancreatic diseases.

Aims/hypothesis Loss of circadian clocks from all tissues causes defective glucose homeostasis as well as loss of feeding and activity rhythms. Little is known about peripheral tissue clocks, so we tested the hypothesis that an intrinsic circadian clock of the pancreas is important for glucose homeostasis. Methods We monitored real-time bioluminescence of pancreas explants from circadian reporter mice and examined clock gene expression in beta cells by immunohistochemistry and in situ hybridisation. We generated mice selectively lacking the essential clock gene Bmal1 (also known as Arntl) in the pancreas and tested mutant mice and littermate controls for glucose and insulin tolerance, insulin production and behaviour. We examined islets isolated from mutants and littermate controls for glucose-stimulated insulin secretion and total insulin content. Results Pancreas explants exhibited robust circadian rhythms. Clock genes Bmal1 and Per1 were expressed in beta cells. Despite normal activity and feeding behaviour, mutant mice lacking clock function in the pancreas had severe glucose intolerance and defective insulin production; their isolated pancreatic islets had defective glucose-stimulated insulin secretion, but normal total insulin content. Conclusions/interpretation The mouse pancreas has an autonomous clock function and beta cells are very likely to be one of the pancreatic cell types possessing an intrinsic clock. The Bmal1 circadian clock gene is required in the pancreas, probably in beta cells, for normal insulin secretion and glucose homeostasis. Our results provide evidence for a previously unrecognised molecular regulator of pancreatic glucose-sensing and/or insulin secretion.

Liver and pancreas progenitors develop from endoderm cells in the embryonic foregut. Shortly after their specification, liver and pancreas progenitors rapidly acquire markedly different cellular functions and regenerative capacities. These changes are elicited by inductive signals and genetic regulatory factors that are highly conserved among vertebrates. Interest in the development and regeneration of the organs has been fueled by the intense need for hepatocytes and pancreatic β cells in the therapeutic treatment of liver failure and type I diabetes. Studies in diverse model organisms have revealed evolutionarily conserved inductive signals and transcription factor networks that elicit the differentiation of liver and pancreatic cells and provide guidance for how to promote hepatocyte and β cell differentiation from diverse stem and progenitor cell types.

The pancreas is a complex organ comprised of three critical cell lineages: islet (endocrine), acinar, and ductal. This review will focus upon recent insights and advances in the biology of pancreatic ductal cells. In particular, emphasis will be placed upon the regulation of ductal cells by specific transcriptional factors during development as well as the underpinnings of acinar-ductal metaplasia as an important adaptive response during injury and regeneration. We also address the potential contributions of ductal cells to neoplastic transformation, specifically in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths worldwide 1 . Studies in human tissues and in mouse models have suggested that for many cancers, stem cells sustain early mutations driving tumour development 2 , 3 . For the pancreas, however, mechanisms underlying cellular renewal and initiation of PDAC remain unresolved. Here, using lineage tracing from the endogenous telomerase reverse transcriptase ( Tert ) locus, we identify a rare TERT-positive subpopulation of pancreatic acinar cells dispersed throughout the exocrine compartment. During homeostasis, these TERT high acinar cells renew the pancreas by forming expanding clones of acinar cells, whereas randomly marked acinar cells do not form these clones. Specific expression of mutant Kras in TERT high acinar cells accelerates acinar clone formation and causes transdifferentiation to ductal pre-invasive pancreatic intraepithelial neoplasms by upregulating Ras–MAPK signalling and activating the downstream kinase ERK (phospho-ERK). In resected human pancreatic neoplasms, we find that foci of phospho-ERK-positive acinar cells are common and frequently contain activating KRAS mutations, suggesting that these acinar regions represent an early cancer precursor lesion. These data support a model in which rare TERT high acinar cells may sustain KRAS mutations, driving acinar cell expansion and creating a field of aberrant cells initiating pancreatic tumorigenesis. A rare population of acinar cells expressing telomerase reverse transcriptase renew the acinar cell compartment during homeostasis, and are potential sources of premalignant cells in pancreatic carcinogenesis.

Skeletal muscle has the capacity to produce, express and release several hundred secreted peptides, so-called myokines. This finding provides a conceptual basis and a new paradigm for understanding the role of skeletal muscle in organ crosstalk, including muscle–liver and muscle–adipose tissue crosstalk. This Review highlights the clinical role of myokines in mediating the multiple health benefits of exercise. During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases. Key Points Myokines are cytokines or other peptides that are produced, expressed and released by muscle fibres Myokines may exert autocrine, paracrine or endocrine effects Myokines may balance and counteract the effects of adipokines The muscle–cell secretome consists of several hundred secreted products Identified myokines include myostatin, LIF, IL-6, IL-7, BDNF, IGF-1, FGF-2, FSTL-1 and irisin Myokines may mediate protective effects of muscular exercise, with regard to diseases associated with a physically inactive lifestyle